Lynch Syndrome-Associated Variants and Cancer Rates in an Ancestrally Diverse Biobank.

Abstract

Limited data are available on the prevalence and clinical impact of Lynch syndrome (LS)-associated genomic variants in non-European ancestry populations. We identified and characterized individuals harboring LS-associated variants in the ancestrally diverse Bio<i>Me</i> Biobank in New York City. Exome sequence data from 30,223 adult Bio<i>Me</i> participants were evaluated for pathogenic, likely pathogenic, and predicted loss-of-function variants in <i>MLH1</i>, <i>MSH2</i>, <i>MSH6</i>, and <i>PMS2</i>. Survey and electronic health record data from variant-positive individuals were reviewed for personal and family cancer histories. We identified 70 individuals (0.2%) harboring LS-associated variants in <i>MLH1</i> (n = 12; 17%), <i>MSH2</i> (n = 13; 19%), <i>MSH6</i> (n = 16; 23%), and <i>PMS2</i> (n = 29; 41%). The overall prevalence was 1 in 432, with higher prevalence among individuals of self-reported African ancestry (1 in 299) than among Hispanic/Latinx (1 in 654) or European (1 in 518) ancestries. Thirteen variant-positive individuals (19%) had a personal history, and 19 (27%) had a family history of an LS-related cancer. LS-related cancer rates were highest in individuals with <i>MSH6</i> variants (31%) and lowest in those with <i>PMS2</i> variants (7%). LS-associated variants were associated with increased risk of colorectal (odds ratio [OR], 5.0; <i>P</i> = .02) and endometrial (OR, 30.1; <i>P</i> = 8.5 × 10^-9) cancers in Bio<i>Me.</i> Only 2 variant-positive individuals (3%) had a documented diagnosis of LS. We found a higher prevalence of LS-associated variants among individuals of African ancestry in New York City. Although cancer risk is significantly increased among variant-positive individuals, the majority do not harbor a clinical diagnosis of LS, suggesting underrecognition of this disease.